Anesthesia is generally administered by physicians or on the order of physicians. Typically, the drugs of choice consist of opioids, benzodiazapines, Propofol and muscle relaxants. These drugs are administered in a variety of ways; for example a particularly determined amount of one or more drugs may be administered parenterally in a single bolus designed to induce a loss of consciousness. Various combinations of drugs are administered so as to achieve a state of muscle relaxation, hypnosis and analgesia. Alternatively, various of these medications may be administered for monitored anesthesia care (MAC), by intermittent boluses or a constant infusion pump. They may be under computer control, patient control, or a combination, (target controlled PCA) wherein a targeted level of anesthesia is preset in the automated control mechanism, with a provision for on-demand patient dosing up to a secondarily determined level. Among the opioids, Alfentanil and Remifentanil are well-known medications, useful as primary analgesics, or in combination with additional medicaments. Monitored anesthesia care (MAC) is possible with a combination of neuroleptic, sedative and analgesic medications. However, physician administered MAC may be associated with underdosing and overdosing, often during the same procedure, on the same patient. This may lead to patient discomfort or prolonged recovery depending on the situation.
The choice of medications is predicated on the speed of onset and offset with which they are metabolized. Administration of long lasting opioids often lead to delays in recovery of mental and respiratory function. Constant vigilance must be maintained during recovery from MAC since respiratory depression and/or cessation of breathing is possible during the recovery period. Alternatively, if a medication is chosen with too short a half-life, and the physician attempts to maintain a very low threshold level, it is possible that drug levels will fall too quickly and the patient will experience pain or untoward effects due to lack of an anesthetic level being maintained. To further compound the matter, the most efficacious mode of administration needs to be chosen. Whether via bolus administration, constant infusion, targeted PCA, or PCA per se, the comfort, safety, and recovery of the patient must be protected and maintained.
Alfentanil, an opioid which has a relatively long half-life, has been used alone and in conjunction with other sedatives, for example hypnotic drugs. Dell et al. utilized an admixture of Alfentanil and Propofol in a PCA modality for patient-controlled sedation during transvaginal oocyte retrieval. Propofol, a powerful sedative having a therapeutic half-life on the order of 3-5 minutes, is often used as an adjunct medication, and is infused in conjunction with other sedatives. The admixture of Alfentanil and Propofol raises the fear of respiratory depression. Because Alfentanil has an elimination half-time of 70-98 minutes and context-sensitive half-time of 12-60 minutes depending on the duration of infusion, Alfentanil may be too long acting for short painful procedures, which are not associated with pain after the procedure. It may lead to prolonged recovery in the PACU or in the worst cases, respiratory arrest when the stimulus is no longer present while the effects of the drugs are still active.
Remifentanil, an ultrashort acting opioid (in the morphine family) with a half-life of only 3 minutes, is marketed under the trade name ULTIVA (TM). Remifentanil has been used for sedation with mixed success. It has been given as an infusion, a bolus medication or a target controlled PCA, where a computer controls the rate of infusion, maintaining a baseline level of anaesthesia while allowing for additional controlled dosing based upon patient demand or lack of demand. Inclusion of Remifentanil in an admixture for a total PCA modality would be counter-intuitive to the skilled practitioner since its short half-life may lead to inadequate pain control. Remifentanil has been used in conjunction with Midazolam (a sedative similar to Valium) using a conventional infusion pump, with a greater degree of success, however, there is some reluctance on the part of physicians due to the constant vigilance required by the physician using a constant dose infusion regimen.
Remifentanil may be a better drug for MAC and PCA due to its rapid onset and rapid offset, however these characteristics render it difficult to maintain overall control and patient satisfaction. Remifentanil has a context-sensitive half-time of 3 minutes, no matter the duration of infusion. Sa et al in 1999 investigated the use of Remifentanil for lithotripsy given as infusion only, infusion+bolus and bolus Remifentanil only. They reported that patient satisfaction and pain control was best in infusion+bolus, and bolus groups but the incidence of transient apneas were also the most common in the group where bolus medications were given. The transient apneas may have been due to the fact that the physicians gave relatively large boluses of Remifentanil and therefore may have transiently overdosed the patients. All study patients also received a bolus dose of Midazolam and an infusion of propofol, which may have affected patient sedation and complication.
It is the premise of the instant inventors that patients are the best judges of adequate pain control and sedation. Although Remifentanil, given as a PCA in small boluses should lead to optimal patient satisfaction and minimal adverse effects, Remifentanil itself will not treat patient anxiety and sedative medication is required for adequate MAC. (Gold 1997). Past attempts at administering combinations of medications have had limited success because they focused on controlling separate and distinct infusions of various of the combinations medicaments. Recognizing this, the present inventors have created a homogeneous blend of Remifentanil and Propofol which provides an optimal sedative effect when administered via a PCA modality.
If a combination of ultra-short acting analgesics and sedatives can be provided which provide an effective level of anesthesia via a PCA modality, prolonged sedation can be avoided in procedures which have minimal or no postoperative pain. By having the patient awake and alert at the end of the procedure, time to discharge from the postoperative care unit (PACU) will be shortened, thereby saving health care resources while minimizing postoperative morbidity.